EP0931063B3 - N-substituierte indol-3-glyoxylamide mit antiasthmatischer, antiallergischer und immunsuppressiver/immunmodulierender wirkung - Google Patents

N-substituierte indol-3-glyoxylamide mit antiasthmatischer, antiallergischer und immunsuppressiver/immunmodulierender wirkung Download PDF

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Publication number
EP0931063B3
EP0931063B3 EP97937586A EP97937586A EP0931063B3 EP 0931063 B3 EP0931063 B3 EP 0931063B3 EP 97937586 A EP97937586 A EP 97937586A EP 97937586 A EP97937586 A EP 97937586A EP 0931063 B3 EP0931063 B3 EP 0931063B3
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Prior art keywords
glyoxylamide
group
pyridin
alkyl
indol
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English (en)
French (fr)
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EP0931063A1 (de
EP0931063B1 (de
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Guillaume Lebaut
Cécilia Menciu
Bernhard Kutscher
Peter Emig
Stefan Szelenyi
Kay Brune
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Ziopharm Oncology Inc
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Ziopharm Oncology Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/22—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an aralkyl radical attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • Indole-3-glyoxylamides are widely used as pharmacodynamically active compounds and as building blocks in pharmaceutical chemistry.
  • NL 6502481 describes compounds that have an anti-inflammatory and antipyretic profile and analgesic activity.
  • GB-PS 1 028 812 find derivatives of indolyl-3-glyoxylic acid and their amides as analgesic, anticonsulsive and ⁇ -adrenergic compounds.
  • EP 0 675 110 A1 are described 1 H-indole-3-glyoxylic acid amides, which are profiled as sPLA2 inhibitors and used in the treatment of septic shock, pancreatitis, in the treatment of allergic rhinitis and rheumatoid arthritis.
  • FR-A-2 689 888 describes perhydroisoindoles which have a specific directed, antagonistic effect.
  • DE-A-1 595 924 describes ⁇ -hydroxy, ⁇ -alkoxy and ⁇ -acyloxy-3-indolylacetic acid compounds containing on the nitrogen atom of the indole ring an acyl radical derived from an aromatic carboxylic acid, (aroyl or heteroaroyl radical) with less than three fused rings, and also their anti-inflammatory effect.
  • the aim of the present invention is to provide novel compounds of the indolyl-3-glyoxylic acid series which have antiasthmatic and immunomodulatory activity.
  • alkyl, alkanol, alkoxy or alkylamino group for the radicals R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 regularly both "straight-chain” and "branched” alkyl groups where "straight-chain alkyl groups" can mean, for example, radicals such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl and "branched alkyl groups” denote, for example, radicals such as isopropyl or tert-butyl.
  • cycloalkyl radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • halogen stands for fluorine, chlorine, bromine or iodine.
  • alkoxy group represents radicals such as methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy or pentoxy.
  • the compounds of the invention may also be present as acid addition salts, for example as salts of mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, salts of organic acids such as acetic acid, lactic acid, malonic acid, maleic acid, fumaric acid, gluconic acid, glucuronic acid, citric acid, embonic acid, methanesulfonic acid, Trifluoroacetic acid and succinic acid.
  • mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid
  • salts of organic acids such as acetic acid, lactic acid, malonic acid, maleic acid, fumaric acid, gluconic acid, glucuronic acid, citric acid, embonic acid, methanesulfonic acid, Trifluoroacetic acid and succinic acid.
  • Both the compounds of formula I and their salts are biologically active.
  • the compounds of formula I can be administered in free form or as salts with a physiologically acceptable acid.
  • the application can be made perorally, parenterally, intravenously, transdermally or by inhalation.
  • the invention relates to pharmaceutical preparations containing at least one compound of formula I or its salt with physiologically acceptable inorganic or organic acids and optionally pharmaceutically acceptable carriers and / or diluents or excipients.
  • Suitable application forms are, for example, tablets, dragees, capsules, solutions or ampoules, suppositories, patches, inhalable powders, suspensions, creams and ointments.
  • the compounds according to the invention exhibit good antiasthmatic, antiallergic and immunosuppressant / immunomodulatory action, for example in transplants and diseases such as psoriasis, rheumatoid diseases and chronic polyarthritis, in the following pharmacological models:
  • mice Male guinea pigs (200-250 g, Dunkin Hartley Shoe) were actively subcutaneously sensitized with ovalbumin (10 ⁇ g ovalbumin + 1 mg Al (OH) 3 ) and boosted 2 weeks later. One week after boosting with ovalbumin, the animals were exposed to inhaled challenge with ovalbumin (0.5% solution) for 20-30 seconds. 24 hours later, the animals were killed by means of an overdose of urethane, bled and a bronchoalveolar lavage (BAL) was performed with 2 x 5 ml of 0.9% saline.
  • ovalbumin 10 ⁇ g ovalbumin + 1 mg Al (OH) 3
  • the lavage fluid was collected and centrifuged at 400 g for 10 minutes, the pellet suspended in 1 ml of 0.9% saline.
  • the eosinophils were counted microscopically in a Neubauerhunt after staining with Becton Dickinson test kit # 5877. This kit contains phloxin B as a selective dye for eosinophils. Eosinophils in the BAL were counted for each animal and expressed as eosinophils (millions / animal). Mean and standard deviation were determined for each group.
  • the animals were treated with a histamine H 1 antagonist (azelastine 0.01 mg / kg po) 2 hours prior to allergen challenge to avoid exitus.
  • a histamine H 1 antagonist azelastine 0.01 mg / kg po
  • the application of the test substances or the vehicle took place 4 hours after allergen challenge.
  • Percent inhibition of eosinophilia in BAL was calculated on groups of 6 - 10 animals.
  • the PPlase activity of cyclophilins was determined enzymatically according to Fischer et. al. (1984). After isomerization of the substrate by the peptidylprolyl isomerase, this is accessible to chymotrypsin, which cleaves the chromophore p-nitroanilines.
  • recombinant human Cyp B was used for the determination of the inhibition of PPiase activity by substance.
  • the interaction of Cyp B with a potential inhibitor was performed as follows: A specific concentration of purified Cyp B was incubated with 1 ⁇ M substance for 15 min. The PPlase reaction was started by adding the substrate solution to the reaction mixture containing HEPES buffer, chymotrypsin, and either test or control samples.
  • Colorimetric Assay (based on the MTT assay) for non-radioactive quantification of cell proliferation and viability
  • MTT is used for the quantitative determination of cell proliferation and activation z.
  • growth factors and cytokines such as IL-2 and IL-4, as well as for the quantitation of antiproliferative or toxic effects.
  • the assay is based on the cleavage of yellow tetrazolium salt MTT to purple formazan crystals by metabolically active cells.
  • the cells grown in a 96-well tissue culture plate, are incubated with yellow MTT solution for approximately 4 hours. After this incubation time, purple formazan salt crystals are formed. These salt crystals are insoluble in aqueous solutions, but can be dissolved overnight by adding solubilizers and incubating the plates.
  • the solubilized formazan product is quantified spectrophotometrically using an ELISA reader
  • An increase in the number of living cells results in an increase in total metabolic activity in the sample. This increase correlates directly with the amount of magenta formazan crystals formed, which are measured by absorbance.
  • substance Inhibition of PPlase activity Inhibition of CD3-induced.
  • IL-2 production Inhibition of Lyinphoproliferation [%] [%] [%] Conc. [ ⁇ M] 0.1 1 10 0.1 1 10 according to Example 1 80 - 100 34 72 95 18 39 61 Cyclosporin A 80 - 100 56 82 94 8th 7 11
  • the indole derivative which may be unsubstituted or substituted at C-2 or in the phenyl skeleton, is dissolved in a protic, dipolar aprotic or nonpolar organic solvent such as isopropanol, tetrahydrofuran, dimethylsulfoxide, dimethylfortnamide, dimethylacetamide, N-methylpyrrolidone, dioxane, Toluene or methylene chloride and added dropwise to a prepared in a three-necked flask under N 2 atmosphere molar or excess suspension of a base such as sodium hydride, powdered potassium hydroxide, potassium tert-butoxide, dimethylaminopyridine or sodium amide in a suitable solvent.
  • a protic, dipolar aprotic or nonpolar organic solvent such as isopropanol, tetrahydrofuran, dimethylsulfoxide, dimethylfortnamide, dimethylacetamide, N-methylpyrrolidone
  • the desired alkyl, aralkyl or. Heteroaralkylhalogenid optionally with the addition of a catalyst such as copper, and allowed to react for some time, for example 30 minutes to 12 hours, maintaining the temperature within a range of 0 ° C to 120 ° C, preferably between 30 ° C to 80 ° C. , especially between 50 ° C and 65 ° C.
  • the reaction mixture is added to water, the solution is extracted, for example, with diethyl ether, dichloromethane, chloroform, methyl tert-butyl ether or tetrahydrofuran, and the organic phase obtained is dried with anhydrous sodium sulfate.
  • the organic phase is concentrated in vacuo, the remaining residue is crystallized by rubbing or by cleaning the oily residue Recrystallization, distillation or by column or flash chromatography on silica gel or alumina.
  • the eluent used is, for example, a mixture of dichloromethane and diethyl ether in a ratio of 8: 2 (v / v) or a mixture of dichloromethane and ethanol in a ratio of 9: 1 (v / v).
  • the N-substituted indole obtained according to the first step of the 1st stage is dissolved under nitrogen atmosphere in an aprotic or nonpolar organic solvent, such as diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, toluene, xylene, methylene chloride or chloroform, to give a Under nitrogen atmosphere prepared solution of a simple molar up to 60 percent excess amount of oxalyl chloride in an aprotic or nonpolar solvent, such as in diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, toluene, xylene, methylene chloride or chloroform, keeping the temperature between -5 ° C and 20 ° C.
  • an aprotic or nonpolar organic solvent such as diethyl ether, methyl tert-butyl ether, tetrahydrofur
  • reaction solution is heated at a temperature between 10 ° C and 130 ° C, preferably between 20 ° C and 80 ° C, especially between 30 ° C and 50 ° C for a period of 30 minutes to 5 hours and then evaporated Solvent off.
  • an aprotic solvent e.g. Tetrahydrofuran, dioxane, diethyl ether, toluene or else in a dipolar aprotic solvent, e.g.
  • Dissolved dimethylformamide, dimethylacetamide or dimethyl sulfoxide to a temperature between 10 ° C and -15 ° C, preferably between -5 ° C and 0 ° C, cooled and treated in the presence of an acid scavenger with a solution of primary or secondary amine in a diluent.
  • Suitable diluents are the solvents used above for dissolving the indolyl-3-glyoxylic acid chloride.
  • acid scavengers find triethylamine, pyridine, dimethylaminopyridine, bas. Ion exchangers, sodium carbonate, potassium carbonate, powdered potassium hydroxide and excess, used for the reaction, primary or secondary amine use.
  • the reaction takes place at a temperature of 0 ° C to 120 ° C, preferably at 20-80 ° C, especially between 40 ° C and 60 ° C instead.
  • the hydrochloride of the acid scavenger is filtered, the filtrate i.Vak.
  • Example 5 N- (pyridin-3-yl) - [1- (2-chlorobenzyl) indol-3-yl] -glyoxylamid
  • Example 6 N- (4-fluorophenyl) - [1- (4-fluorobenzyl) indol-3-yl] -glyoxylamid
  • Example 7 N- (4-Nitrophenyl) - [1- (4-fluorobenzyl) indol-3-yl] -glyoxylamid
  • Example 8 N- (2-chloropyridin-3-yl) - [1- (4-fluorobenzyl) indol-3-yl] -glyoxylamid
  • Example 9 N- (pyridin-4-yl) - (1-benzylindole-3-yl) -glyoxylamid
  • the reaction solution is then heated for 1 to 5 hours at a temperature between 10 ° C and 120 ° C, preferably between 20 ° C and 80 ° C, especially between 30 ° C and 60 ° C and then the solvent evaporated.
  • the remaining residue of (indol-3-yl) glyoxylic chloride is dissolved or suspended in an aprotic solvent, such as tetrahydrofuran, dioxane, diethyl ether, toluene or in a dipolar aprotic solvent such as dimethylformamide, dimethylacetamide or dimethyl sulfoxide, to a temperature between -10 ° C and + 10 ° C, preferably cooled to -5 ° C to 0 ° C and treated in the presence of an acid scavenger with a solution of the primary or secondary amine in a diluent.
  • an aprotic solvent such as tetrahydrofuran, dioxane, diethyl ether, tol
  • Suitable diluents are the solvents used to dissolve the "indolyl-3-glyoxylic acid chloride" Question.
  • acid scavengers find triethylamine, pyridine, dimethylaminopyridine bas.
  • the reaction takes place at a temperature of 0 ° C to 120 ° C, preferably at 20-80 ° C, especially between 40 ° C and 60 ° C. After reacting for 1-4 hours and standing at room temperature for 24 hours, it is filtered, the precipitate digested with water, filtered with suction and i. Vak. dried.
  • the desired compound is purified by recrystallization in an organic solvent or by column chromatography on silica gel or alumina.
  • the eluent is, for example, a mixture of dichloromethane and ethanol (10: 1, vol / vol) use.
  • the "Indol-3-yl-glyoxylamide" obtained in the first step of the first step is dissolved in a protic, dipolar aprotic or non-polar organic solvent, such as, for example, isopropanol, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dioxane, toluene or methylene chloride and dropwise added to a prepared in a three-necked flask under N 2 atmosphere molar or excess suspension of a base such as sodium hydride, powdered potassium hydroxide, potassium tert-butoxide, dimethylaminopyridine or sodium amide in a suitable solvent.
  • a protic, dipolar aprotic or non-polar organic solvent such as, for example, isopropanol, tetrahydrofuran, dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidon
  • Heteroaralkylhalogenid either undiluted or in a diluent, for example, was also used to solve the "indol-3-yl-glyoxylamids", optionally with the addition of a catalyst such as copper, and allowed to react for some time, for example, 30 minutes to 12 hours and maintains the temperature within a range between 0 ° C and 120 ° C, preferably between 30 ° C and 80 ° C, especially between 50 and 70 ° C.
  • the reaction mixture is poured into water, the solution is extracted, for example, with diethyl ether, dichloromethane, chloroform, methyl tert-butyl ether, tetrahydrofuran or n-butanol and the respectively obtained organic phase dried with anhydrous sodium sulfate.
  • the organic phase is concentrated in vacuo, the remaining residue is crystallized by trituration or the oily residue is purified by distillation or by column or flash chromatography on silica gel or alumina.
  • the eluent used is, for example, a mixture of methylene chloride and diethyl ether in a ratio of 8: 2 (v / v) or a mixture of methylene chloride and ethanol in a ratio of 9: 1 (v / v).
  • Example 28 N- (4-nitrophenyl) - [1- (4-fluorobenzyl) -indol-3-yl] -glyoxylamide (final stage, identical to Example 7)
  • Example 29 N- (4-fluorophenyl) - [1- (4-fluorobenzyl) -indol-3-yl] -glyoxylamide (final stage, identical to Example 6)
  • Example 30 N- (pyridin-3-yl) - [1-4-fluorobenzyl) -indol-3-yl] -glyoxylamide (final stage, identical to example 3)

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
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  • Pain & Pain Management (AREA)
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  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)
EP97937586A 1996-09-06 1997-08-16 N-substituierte indol-3-glyoxylamide mit antiasthmatischer, antiallergischer und immunsuppressiver/immunmodulierender wirkung Expired - Lifetime EP0931063B3 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19636150 1996-09-06
DE19636150A DE19636150A1 (de) 1996-09-06 1996-09-06 N-substituierte Indol-3-glyoxylamide mit antiasthmatischer, antiallergischer und immunsuppressiver/immunmodulierender Wirkung
PCT/EP1997/004474 WO1998009946A1 (de) 1996-09-06 1997-08-16 N-substituierte indol-3-glyoxylamide mit antiasthmatischer, antiallergischer und immunsuppressiver/immunmodulierender wirkung

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EP0931063A1 EP0931063A1 (de) 1999-07-28
EP0931063B1 EP0931063B1 (de) 2006-10-18
EP0931063B3 true EP0931063B3 (de) 2009-04-08

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Publication number Priority date Publication date Assignee Title
DE19636150A1 (de) * 1996-09-06 1998-03-12 Asta Medica Ag N-substituierte Indol-3-glyoxylamide mit antiasthmatischer, antiallergischer und immunsuppressiver/immunmodulierender Wirkung
CN1205207C (zh) * 1998-03-31 2005-06-08 药品发现学会公司 取代的吲哚链烷酸
DE19814838C2 (de) * 1998-04-02 2001-01-18 Asta Medica Ag Indolyl-3-glyoxylsäure-Derivate mit Antitumorwirkung
DE19946301A1 (de) 1998-04-02 2001-04-19 Asta Medica Ag Indolyl-3-glyoxylsäure-Derivate mit therapeutisch wertvollen Eigenschaften
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US6008231A (en) 1999-12-28
DE59712752D1 (de) 2006-11-30
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ES2276433T3 (es) 2007-06-16
CN1227542A (zh) 1999-09-01
AR008630A1 (es) 2000-02-09
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US6344467B1 (en) 2002-02-05
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HK1123280A1 (en) 2009-06-12
US20030207892A1 (en) 2003-11-06
KR20000068495A (ko) 2000-11-25
WO1998009946A1 (de) 1998-03-12
CN101219985A (zh) 2008-07-16
BR9712808B1 (pt) 2009-05-05
NO20030481L (no) 1999-03-04
CZ61699A3 (cs) 1999-06-16
AU726521B2 (en) 2000-11-09
KR100516321B1 (ko) 2005-09-23
NO314725B1 (no) 2003-05-12
NO991071D0 (no) 1999-03-04
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TW550256B (en) 2003-09-01
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JP2000505098A (ja) 2000-04-25
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RU2237661C2 (ru) 2004-10-10
DE19636150A1 (de) 1998-03-12
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US20020161025A1 (en) 2002-10-31
EP0931063A1 (de) 1999-07-28
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ATE342889T1 (de) 2006-11-15
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US6919344B2 (en) 2005-07-19
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